PROJECT SUMMARY/ABSTRACT HIV+ adults who drink are already physiologically frail due to HIV infection, comorbidity (including hepatitis C infection), polypharmacy and associated substance use. In this setting, biomedical consequences of alcohol use can occur with moderate use and are often unappreciated or misattributed. The ?Consortium to improve OutcoMes in HIV/Aids, Alcohol, Aging & multi-Substance? (COMpAAAS) is supported by NIH/NIAAA award U24AA020794 to study this issue in a single sample, the Veterans Aging Cohort Study (VACS) (~50,000 HIV+ US veterans demographically matched to ~100,000 uninfected comparators). VACS will employ a direct alcohol biomarker (Phosphatidyl-ethanol [PEth] and a validated measure of physiologic frailty (VACS Index). In this set of three applications, the Antiretroviral Therapy Cohort Collaboration (ART-CC) and Kaiser Permanente (KP) teams join the Veterans Healthcare System (VA) team as COMpAAAS Tripartite: ART-CC, KP, and VA. Our long term goal is to inform alcohol intervention design and implementation. Together we propose to study biomedical consequences of alcohol and associated substance use in HIV, extending the scope and generalizability of VACS to multiple healthcare systems in North America and Europe and substantially increasing sample size and diversity of HIV+ subjects. Importantly, COMpAAAS Tripartite also expands the sample of uninfected comparators, a critically important group if we are to understand how alcohol differentially affects biomedical outcomes in HIV. KP will be able to identify demographically-matched uninfected comparators from their Northern California region. A new VA sample of veterans born in 1945-1965 (Birth Cohort) expands access to Hepatitis C infected (HCV+) and women comparators. The tripartite group will also participate in an HIV+ substudy (n=2250), The Medications, Alcohol, Substance Use in HIV Study (MASH), in which new data on potentially inappropriate medications (PIMS) and biomarkers for alcohol and substances (tobacco, marijuana, opioids, cocaine, and methamphetamine) will be collected. As the lead site for Aim 2, KP will examine the impact of alcohol and smoking on HIV outcomes, preventive care, and medical comorbidities. We anticipate that among HIV+ individuals, hazardous alcohol use, alcohol use disorders and smoking will negatively impact each of these outcomes; and that these effects will be amplified in HIV+ individuals compared with uninfected individuals. Initially, analyses will use electronic health record data including self-reported alcohol and substance use. Analyses will be repeated in the final year correcting for biases in self-reported alcohol and substance use based upon MASH results. Consistent with the RFA, all grants contribute data for all aims, have identical aims and protocols. This application addresses key interactions between alcohol and tobacco use, antiretrovirals, and medications that may increase mortality, hospitalization, frailty, and adversely impact preventive health care. We anticipate findings may lead to innovative intervention development, such as combined alcohol, smoking and preventive care interventions.